Augmentation of anti-tumor immunity by adoptive T-cell transfer after allogeneic hematopoietic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (HCT) is currently the standard of care for most patients with high-risk acute leukemias and some other hematologic malignancies. Although HCT can be curative, many patients who undergo allogeneic HCT will later relapse. There is, therefore, a critical need for the development of novel post-HCT therapies for patients who are at high risk for disease recurrence following HCT. One potentially efficacious approach is adoptive T-cell immunotherapy, which is currently undergoing a renaissance that has been inspired by scientific insight into the key issues that impeded its previous clinical application. Translation of the next generation of adoptive T-cell therapies to the allogeneic HCT setting, using donor T cells of defined specificity and function, presents a unique set of challenges and opportunities. The challenges, progress and future of adoptive T-cell therapy following allogeneic HCT are discussed in this review. Keywords allogeneic transplantation; central memory; graft versus leukemia; immunotherapy; T cellsAllogeneic hematopoietic stem cell transplantation (HCT) can be curative and is the standard of care for many chemotherapy-refractory and high-risk hematologic malignancies including acute myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia (CLL), non-Hodgkin's lymphoma and Hodgkin's lymphoma. Unfortunately, a significant fraction of patients who undergo allogeneic HCT will later relapse, and the development of novel post-HCT therapies for patients who are at high risk for disease recurrence following

Boost and loss of immune responses against tumor-associated antigens in the course of pregnancy as a model for allogeneic immunotherapy

“…Although nonrelapse mortality rates in allogeneic hematopoietic stem cell transplantation (HSCT) have declined steadily over time, relapse rates remain consistently high. 32,33 Thus, current research in allogeneic HSCT focuses on the enhancement of GVL effects to optimize disease control. 32,34 However, the appearance of severe GVHD requiring immediate immunosuppression regularly compromises these beneficial effects of the allograft.…”

“…32,33 Thus, current research in allogeneic HSCT focuses on the enhancement of GVL effects to optimize disease control. 32,34 However, the appearance of severe GVHD requiring immediate immunosuppression regularly compromises these beneficial effects of the allograft. 35,36 Consequently, several immunotherapeutic approaches nowadays focus on TAAs as target antigens to mount antileukemic immune responses in the absence of GVHD.…”

Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation

“…Clinical responses were observed, indicating that redirected T cells might be effective against cancer; response rates, however, were suboptimal compared with responses observed upon infusion of naturally occurring tumor‐specific T cells . Although initially tested in the autologous setting, TCR gene transfer might also increase the efficacy of DLI in the context of allo‐HSCT .…”

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

“…1 In patients undergoing allogeneic HSCT, donor-derived T-cell activation leads to widespread host tissue damage, resulting in a clinicopathologic syndrome known as graft-versus-host disease (GVHD). 2 However, T cell-mediated attack of the recipient can also be beneficial because it can eliminate malignant cells that might have escaped radiation or chemotherapy, a process known as the graft-versus-tumor (GVT) effect.…”